Chronic obstructive pulmonary disease (COPD) is a highly prevalent but heterogeneous disorder, particularly with respect to disease progression. Thoracic imaging holds promise for characterizing disease heterogeneity but is limited by the inability to resolve emphysema and small airways disease. Small airways disease is the primary site of airflow obstruction in COPD and precedes the development of emphysema. There remains a critical need to non-invasively characterize the pathologic heterogeneity of COPD, particularly at an early stage in order to develop targeted therapies. We recently developed the Parametric Response Map (PRM capable of assessing functional small airways disease (fSAD) and emphysema. Our preliminary data suggest that PRM: a) identifies abnormality even in those without spirometric obstruction; b) fSAD is the predominant lesion in mildly obstructed patients whereas emphysema predominates in more severely obstructed subjects; c) and fSAD precedes the development of CT defined emphysema. We hypothesize that PRM metrics will allow us to non-invasively evaluate the regional structural heterogeneity of airflow obstruction and its relationship to clinically relevant outcomes. To test this hypothesis we plan to leverage two NHLBI cohorts. The first is the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a 3,200 subject study where a baseline and one-year CT are already included in the protocol linked to extensive clinical and biologic data; this proposal will also fund an additional 200 three-year CT's. The second is COPDGene, a 10,000 subject study with baseline and five year CTs. We will also take advantage of the active lung transplant programs at the University of Michigan and Temple University to obtain explants for this proposal. We plan to test our central hypothesis by pursuing the following three specific aims: (1) determine whether PRM fSAD precedes the development of emphysema and lung function decline by performing PRM on baseline, 1-year and 3-year CT images; (2) determine the relationship between PRM metrics and clinical outcomes including acute exacerbations of COPD; and (3) determine relationship between the extent of histological abnormality in the small airways and the emphysema with PRM metrics from the same patients. it is our expectation that PRM fSAD will identify COPD patients at risk for more rapid disease progression and histologically verified small airways disease. Such results could both identify patients appropriate for more intense, targeted therapy at an early disease stage and contribute to our understanding of the progression of small airways disease and emphysema in COPD and its relationship to important clinical outcomes.